rs199682486

Positions:

chr1-63402348-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_013339.4(ALG6):c.257+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000859 in 1,591,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00088 ( 0 hom. )

Consequence

ALG6
NM_013339.4 splice_donor_5th_base, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21

Conservation

PhyloP100: 9.55

Variant links:

Genes affected

ALG6 (HGNC:23157): (ALG6 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. Mutations in this gene are associated with congenital disorders of glycosylation type Ic. [provided by RefSeq, Jul 2008]

ALG6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 1-63402348-G-A is Pathogenic according to our data. Variant chr1-63402348-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 95529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-63402348-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALG6	NM_013339.4 linkuse as main transcript	c.257+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000263440.6	NP_037471.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALG6	ENST00000263440.6 linkuse as main transcript	c.257+5G>A		splice_donor_5th_base_variant, intron_variant		5	NM_013339.4	ENSP00000263440	P1

Frequencies

GnomAD3 genomes

AF:

0.000615

AC:

AN:

151150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000475

AC:

119

AN:

250774

Hom.:

AF XY:

0.000516

AC XY:

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000936

Gnomad NFE exome

AF:

0.000960

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000884

AC:

1273

AN:

1439864

Hom.:

Cov.:

AF XY:

0.000862

AC XY:

618

AN XY:

717262

show subpopulations

Gnomad4 AFR exome

AF:

0.0000909

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.0000388

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000574

Gnomad4 NFE exome

AF:

0.00113

Gnomad4 OTH exome

AF:

0.000471

GnomAD4 genome

AF:

0.000615

AC:

AN:

151150

Hom.:

Cov.:

AF XY:

0.000570

AC XY:

AN XY:

73744

show subpopulations

Gnomad4 AFR

AF:

0.000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00122

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000733

Hom.:

Bravo

AF:

0.000669

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALG6-congenital disorder of glycosylation 1C

Pathogenic:13

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Mar 30, 2016	The c.257+5G>A splicing variant in the ALG6 gene has been previously reported in individuals affected with autosomal recessive congenital disorder of glycosylation Ic, and in trans with a known pathogenic variant (Imbach et al. 2000 and Westphal et al. 2000). This variant is shown to cause the skipping of exon 3, and produces a nonfunctional enzyme as shown by its inability to restore normal glycosylation in a yeast strain lacking a functional ALG6 (Westphal et al. 2000). This c.257+5G>A has been reported in very low frequency in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAc) and has been reported pathogenic in the Emory Genetic Patient Database. Therefore, this collective evidence supports the classification of the c.257+5G>A as a recessive pathogenic variant for congenital disorder of glycosylation type Ic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 01, 2021	NM_013339.3(ALG6):c.257+5G>A is an intronic variant classified as likely pathogenic in the context of congenital disorder of glycosylation type Ic. c.257+5G>A has been observed in cases with relevant disease (PMID: 27287710, 27959697). Functional assessments of this variant are available in the literature (PMID: 10924277, 10914684). c.257+5G>A has been observed in population frequency databases (gnomAD: NFE 0.09%). In summary, NM_013339.3(ALG6):c.257+5G>A is an intronic variant that has functional support for pathogenicity and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change falls in intron 4 of the ALG6 gene. It does not directly change the encoded amino acid sequence of the ALG6 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs199682486, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with congenital disorder of glycosylation 1c (PMID: 10914684, 10924277, 20447155, 23430515). This variant is also known as IVS3+5G>A. ClinVar contains an entry for this variant (Variation ID: 95529). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 10924277). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 17, 2023	Variant summary: ALG6 c.257+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing, including three that predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, resulting in a skipping of exon 3 (Imbach_2000). The variant allele was found at a frequency of 0.00047 in 250774 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALG6 causing Congenital Disorder Of Glycosylation Type 1C (0.00047 vs 0.0011), allowing no conclusion about variant significance. c.257+5G>A has been reported in the literature in multiple compound heterozygous individuals affected with Congenital Disorder Of Glycosylation (Abu Bakkar_2022, Imbach_2000, Morava_2016, Westphal_2000), some of whom were reported to have other (likely) pathogenic variants of ALG6 in trans. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating the effect of transforming ALG6 missing exon 3 in an alg6-deficient strain of S. cerevisiae, finding that it is unable restore glycosylation activity (Westphal_2000). 12 submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital disorder of glycosylation, type Ic (MIM#603147). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been proven to cause in-frame skipping of exon 3 (PMID: 10924277). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (103 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple patients with congenital disorder of glycosylation, type Ic (ClinVar, PMID: 10924277). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 22, 2015	- -

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2023	Functional studies indicate that c.257+5G>A (reported using alternate nomenclature IVS3+5G>A) transfected cells produce a nonfunctional enzyme that is unable to restore normal glycosylation in a yeast strain lacking functional ALG6 (Westphal et al., 2000); Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 21541726, 23430515, 20447155, 10914684, 27959697, 10924277, 27287710, 31980526, 31589614, 35279850, 36756224) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 28, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2020

The c.257+5G>A intronic alteration results from a G to A substitution 5 nucleotides after exon 4 (coding exon 3) of the ALG6 gene. Based on data from the Genome Aggregation Database (gnomAD) database, the ALG6 c.257+5G>A alteration was observed in 0.05% (133/282026) of total alleles studied, with a frequency of 0.09% (121/128932) in the European (non-Finnish) subpopulation. This alteration has been detected in trans with another mutant allele in multiple patients with clinical and biochemical features of congenital disorder of glycosylation 1c (Westphal, 2000; Drijvers, 2010). This nucleotide position is highly conserved in available vertebrate species. Functional studies demonstrate that this alteration causes skipping of coding exon 3 leading to a nonfunctional protein (Imbach, 2000; Westphal, 2000). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

ALG6-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

The ALG6 c.257+5G>A variant is predicted to interfere with splicing. This variant has been reported as pathogenic for autosomal recessive congenital disorder of glycosylation type Ic (CDG-Ic) due to alpha-1,3 glucosyltransferase deficiency (Imbach et al. 2000. PubMed ID: 10914684; Westphal et al. 2000. PubMed ID: 10924277; Drijvers et al. 2010. PubMed ID: 20447155; Dercksen et al. 2013. PubMed ID: 23430515). This variant is reported in 0.094% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Functional studies have demonstrated this variant leads to exon skipping (Westphal et al. 2000. PubMed ID: 10924277). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.92

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.92

Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over